Manufactured nanomaterials are found in cosmetics, lotions, coatings, and used in environmental remediation applications. Therefore, there exists a large opportunity for exposure through many different routes, thus, making it necessary to study the health implications of these materials. The primary objective of this research is to fully integrate studies of the physical and chemical properties of commercially manufactured nanoparticles with inhalation toxicological studies of these same nanoparticles to determine those properties that most significantly affect nanoparticle toxicity. Our central hypothesis is that nanoparticle physico-chemical properties differ widely among particle types and certain properties induce adverse health outcomes. Furthermore, we hypothesize that nanoparticle toxicity is influenced by the susceptibility of the individual as well as the presence of other inflammatory substances. We will address these hypotheses through a series of specific study aims designed to establish a relationship between nanoparticle physicochemical properties and health outcomes. Specific Aim 1. Evaluate nanoparticle chemical composition (bulk and surface) on nanoparticle toxicity in acute and sub-acute exposure studies. Experiments will be designed to investigate nanoparticle composition (bulk and surface) before and during and after inhalation exposure studies. Specific Aim 2. Determine the impact of nanoparticle physical morphology (agglomeration size, agglomeration state and nanoparticle shape) on nanoparticle toxicity. This study will incorporate animal inhalation studies to determine the relationship between nanoparticle agglomerate size and nanoparticle shape on toxicity. Specific Aim 3: Determine if pulmonary clearance is impaired by inhaled nanoparticles and if impaired clearance increases the risk of pulmonary infection. The pulmonary clearance mechanism, especially the ability of alveolar macrophages to clear microbes or foreign particles, can be impaired by inhaled particulates. In this aim, we will compare lung clearance rates after inhalation of nanoparticles of different composition. Specific Aim 4: Compare lung inflammation produced by co-exposure of nanoparticles with other inflammatory substances and relative to the nanoparticles alone. We plan to evaluate synergistic effects with other common aerosols present in the indoor and outdoor environments including endotoxins and sulfate aerosols (e.g. ammonium sulfate). FOR PUBLIC: Manufactured nanomaterials are becoming more widespread and can found in cosmetics, lotions, coatings, and used in environmental remediation applications. The studies described here will help answer questions as to the potential impact of manufactured nanomaterials on public health as there is clearly a lack of information in this regard. These studies will focus on determining the properties that make some nanoparticles more toxic than others.